The present invention relates to medical implants made in part or in all of formable, pyromellitic, dianhydride (PMDA)-free, non-halogenated, aromatic polyimide, process for manufacturing the implants and method of implanting the implants in subjects in need. More particularly, the present invention relates to orthopedic implants made in part or in all of formable, pyromellitic, dianhydride (PMDA)-free, non-halogenated, aromatic polyimide, process for manufacturing the orthopedic implants and method of implanting the orthopedic implants in subjects in need.
Synthetic bio-compatible materials have been used in a wide range of medical and dental applications. Since the earliest uses of gold strands as soft tissue sutures for hernia repairs (around 1000 B.C.), silver and gold artificial dental crowns, and gemstones as tooth replacements (inserted into bone and extending into the oral cavity), bio-compatible materials have evolved to standardized formulations.
Since the late 1930s, high-technology polymeric, ceramic, metallic and composite substrates have played a central role in expanding the application of biocompatible materials-made medical devices.
Plastics hold an important position in the field of medicine as structural materials implanted in the body and as surgical aids. Plastic materials are preferred over metals and ceramics due to their low specific weight, high mechanical strength (as evaluated on a strength-to-weight basis), toughness and chemical inertness and hence stability. Plastic materials are also readily shaped and machined and are commercially available in diverse forms and structures.
Structural plastics are used for permanent endo- or exo-prostheses. Other applications of plastic materials in medicine are blood tubing, heart valves, artificial cornea, artificial heart and kidney components, artificial joints and bone, encapsulants for implanted electrical devices such as pacemakers, flexible circuits, etc.
The advent of orthopedic implants is possibly one of the greatest advances of the past century in orthopedic surgery. The concept of introducing an artificial joint became possible only when new materials and fixation methods were developed and applied by successful collaboration of materials scientists, engineers and surgeons. A joint replacement should have the great advantage of providing pain-free and as smooth as possible movement for the patients, mimicking, as much as possible, the functionality and movements repertoire of the respective natural joint.
In the case of an endo-prosthesis, where two bearing surfaces are replaced by artificial prostheses (made of either similar or different materials), thus creating an artificial joint, high friction and wear problems may occur over a period of time, depending, to a great extent, on the patient""s activity.
In the orthopedic joint endo-prosthesis(1), three basic conditions are necessary for successful total arthroplasty: (i) bio-compatibility with the surrounding tissues; (ii) good adhesion and stable fixation of the endo-prosthesis to the bone; and (iii) negligible friction without formation of wear debris of the joint elements during service under dynamic load. Large frictional forces in the hinged joint and tendency of the implant material to spall and delaminate can cause loosening of the construction and creation of wear debris, which lead to acute or chronic inflammation.
A natural joint is a connection between two bones and is classified in two fundamental types(16): (i) joints lacking a joint cavity, which allow little or no movement, for example the joint between adjacent vertebrae and the joint between the ribs and sternum; and (ii) joints having a joint cavity, which constitute the freely movable joints of the body, and are called the synovial joints. Depending on their position in the body, synovial joints have evolved to permit one or more of the following types of movements: flexion, extension, abduction, adduction, rotation and circumduction. In the human body, there are six kinds of synovial joints: ball and socket, hinge, pivot, ellipsoidal, saddle and gliding.
Continuous friction and accelerated wear of two contacted non-lubricated surfaces moving one with respect to the other are the result of the interaction of asperities or surface roughness. When two surfaces are rubbed together under load, asperities on the two surfaces may adhere, and relative sliding movement will then be possible only if the adhesive forces are overcomed by shear forces. Unless the shearing takes place exactly along the original interface, material will be removed, resulting in what is known as adhesive wear.
Cyclic variations under load, or cyclic movements of a bearing under constant load, impose dynamically varying stresses on the elements of the material. Such dynamically varying stresses may cause fatigue fractures at, or close to the surface, thereby promoting particle detachment. This process is known as fatigue wear.
Lubrication minimizes frictional resistance between bearing surfaces by keeping them apart. Fluid and boundary lubrication(17) are probably the most important mechanisms preventing cartilage wear under high loads in natural joints. It will be appreciated in this respect that, the coefficient of friction in a synovial joint is about 0.001-0.01, while typical dry coefficient of friction of plastic on plastic is about 0.1-0.3 and for metal on metal about 0.3-0.8, rendering these materials poor substitutes.
Several families of materials such as polymers, metals, ceramics and composite materials were tested as potential implant materials for hip and knee arthroplasty. Due to the harsh environment of the human body fluids and the frequent movement of these parts, the useful lifetime of these implants is about less than 10 years. Thus, a replacement implant is needed which involves repeated (once or more) surgery (depending on the age and activity of the patient). Fractures and wear of the implant are clearly observed. The wear debris produced by friction from the damaged implants circulate in the body or stay in the tissues and cause inflammation. In order to solve this problem a low friction, wear-resistant material is needed.
The majority of total hip prostheses currently implanted consists of a hard metal, or ceramic femoral head placed against a cross-linked or uncross-linked ultra-high-molecular weight-polyethylene (UHMWPE) acetabular cup with or without cement fixation. Currently, more than 500,000 artificial hips are implanted annually, worldwide. The low-friction, low-wear un-crosslinked UHMWPE has been considered for the last two decades as the best polymeric solution for total artificial hip implants. Notwithstanding the success, over the last 10 years these prostheses exhibited frequent failures, due to late aseptic loosening, creep, migration and inflammation, resulting in the need to be revised through surgery. No implant survived more than 25 years, while most of the implants lasted less than 10 years, typically 5 to 7 years.
The following materials have been used to form artificial medical implants over the years:
Teflon(copyright)(2) is a material known to cold flow, namely, irreversibly deform over time under loading. It failed due to mechanical wear (80%), infection (10%) and metal femoral head penetration, absorption of great masses of the surrounding bone and implanted material.
Silicone(14) prostheses are used in finger and toe joints. Fatigue fractures occurrence and the low durability of this material results in weak bonding which leads to particles release.
UHMWPE(3-5) promotes bone lysis (Periprosthetic Osteolysis) due to release of submicron size debris into the surrounding soft tissues as a result of wear. The body reacts by xe2x80x9cactivatingxe2x80x9d macrophages that attack the particles and release biochemical mediators in the bone implant interface, causing inflammation and loosening. The UHMWPE implant degrades in the body, chips off, exposes the base metal and becomes released from the cemented fixation. There are 20-30% cases of failure within 5-7 years of implantation that call for replacement.
Cross-linked UHMWPE(2) is a new modified version of UHMWPE which shows less wear than UHMWPE, thus longer term of service, but still has a risk of wear debris stimulated osteolysis. There is a risk of post oxidation of the UHMWPE by the Gamma irradiation during the cross-linking process, releasing free radicals. This oxidation weakens the material and causes embrittlement during aging. UHMWPE is stiffer and more prone to water absorption which would affect the mechanical properties and tribology of the material.
Ceramic implants(6) are composed of Alumina and Zirconia and are mostly used in Europe. Ceramic has excellent bio-compatibility, good surface finish, low friction and hence low wear and high hardness. The drawbacks of ceramic implants are low fracture toughness, low impact strength and brittleness-causing fragmentation and cracking of the implants. Failures include femoral head fractures and catastrophic breakage of ceramic sockets. Improved performance greatly depends upon careful surgical techniques with precise positioning of the prosthesis. Failure to correctly position this type of implant results in massive wear and the onset of osteolysis between the femoral neck and the rim of the acetabular cup. Small sharp edged particles (5 micron) and smaller granular debris (0.4 microns) have been found in macrophages near the surface of the implant. Zirconia wear debris is more frequent than that of alumina. Osteolysis appeared after a mean implantation time of 92 months. Loosening and migration of acetabular components were also found, which required replacement. The ceramic wear debris stimulates a foreign body response. Other disadvantages of ceramics are the high specific density (causing elevated weight of the implant compared to plastics) and accelerated stress hydrolysis in humid environment once the surface is violated through mechanical stress causing crack formation in wet environment and fracture (stress corrosion).
Metal implants(5-7) consist mostly of CoCrMo alloy which exhibits low wear (40-100 times lower than UHMWPE), good surface finish and high mechanical properties. The drawbacks of metals are metallic electrochemical corrosion risk (low bio-compatibility) accelerated by the ions present in the body fluids and the presence of oxygen. These conditions generate chemically active and toxic degradation products, and produce wear particles. The wear particles are very small (mostly 10-25 nm in diameter) but the number of particles exceeds those of UHMWPE (10 to 500 times more). The small size and large number of the particles raise a new issue of remote distribution in the human body and the biologically effects on various cells and tissues. Some particles may even attach or dissolve in the lymphatic vessels. The hematological spread of the metal particles may access any tissue in the body, such as liver, kidney and even the brain. Metal debris in the lymph nodes causes structural changes including necrosis and fibrosis. There is an increased risk of development of tumors of the lymphatic system (carcinogenic potential). The level of inflammation depends on the amount, size and shape of the debris.
Hyper-sensitivity of the body to metal ions release is another problem. Metal ions may bind to body proteins when they are released from the metal implant. Metal ions bound to proteins induce T lymphocyte response leading to hypersensitivity reactions. Another problem is the toxicity of the metal ions (Co and Cr). Co and Cr ions, which reduce cell viability even at low concentrations, are toxic to osteoblast cells by inhibiting their differentiation. Titanium is a much lighter metal but is a poor bearing material. It wears fourfold more than CoCr and is toxic as well. It activates macrophages and causes osteolysis. Compared to polymers, metal prostheses are substantially heavier.
Composite material implants such as polymer mixed with glass or carbon fibers have been tested as implant material without success. Glass fibers deteriorate at humid environment and carbon fibers tend to circulate, causing inflamation. The surface of such implants is not smooth because of the fibers which cause porosivity. Presently, such composite materials are not used as implants.
Polyimides:(15),(20) 
It is known that aromatic polyimides (PI) form an important class of high performance polymers because of their many desirable characteristics such as: mechanical strength, low dielectric constant, good processability, e.g., in processes such as injection or compression molding, wear and radiation resistance, chemical inertness, e.g., inertness to solvents, good adhesion properties, low thermal expansion (as a plastic), thermal stability and long term durability. PI with desired properties can be produced by manipulation of both monomer selection and process engineering. Thus, there is a wide scope of applications for PI, including; aerospace, microelectronics, opto-electronics, fiber optics, etc.
There are known PIs, such as, for example, Kapton(copyright), (which is fabricated as a film and cannot be molded) and Vespel(copyright) (which can be molded) that integrate pyromellitic dianhydride (PMDA) group as one of their monomers. This chemical moiety (the PMDA group) which is integrated within the polymer chain by displacement of the oxygen of the two anhydride groups (forming an imide bond) is susceptible to hydrolysis. Since it is hydrolizable, it could rapidly degrade in the body, especially under wear and friction.
Amstutz(19) has suggested using Vespel(copyright) (a PMDA-containing aromatic polyimide compound) as a possible bearing material for orthopedic use. It was compared to UHMWPE (creeps and deforms under load+cold flows) and to Teflon(copyright) (severe wear and cold flow). Vespel(copyright) has the same density and same modulus as bone, has good elasticity and damping of shock forces, has high strength to weight ratio, can be molded and machined and has sufficient wear and creep resistance. However, toxicological aspects have never been tested. Furthermore, due to the presence of a PMDA group in Vespel(copyright), this material is likely to undergo hydrolysis in the body, especially under wear and friction conditions.
Due to this shortcoming, the PI polymers which contain the PMDA group, are not applicable in orthopedic implantation procedures. However, these PIs have been used as implants in other, less demanding, medical and clinical applications as described hereinafter.
Among the known PMDA-containing PIs and PIs which contain halogens and aliphatic units that are used as implants in non-orthopedic medical applications, are:
1. KAPTON(copyright)(12)2. HUGHES HR 610(copyright)(9) 
2. DuPont 2555(copyright)(9) 
3. Hitachi PIQ(copyright)(9) 
4. MandT 2056/5000(copyright)(9) 
5. DuPont SP1(copyright)(9) 
6. DuPont SP21(copyright)+15% graphite(10) 
7. Amoco AI(copyright) (Polyimide-Amide)(10) 
8. 6FDA-DDS(copyright)(13) 
(IM-PH-C(CF3)2-PH-IM-PH-SO2-PH)n 
9. 6FDA-6FAP(copyright)(13)
(IM-PH-C(CF3)2-PH-IM-PH-S(CH3)2-PH)n 
10. 6FDA-APPS(copyright)(13) 
(IM-PH-C(CH3)2-PH-IM-PH-Oxe2x80x94SO2-PH-O-PH)n 
11. SILTEM1500(copyright)(12) 
IM-O-IM-(CH2)3xe2x80x94Sixe2x80x94(CH3)2xe2x80x94)n xe2x80x94Oxe2x80x94Si(CH3)2xe2x80x94(CH2)3-IM-O-IM-PH-CH2-PH 
12. ULTEM 1010(copyright)(12) 
13. Polyimide film(18) 
wherein in the above compounds, IM=imide group; and PH=Phenylene group.
The above listed polyimides are biocompatible but have not or cannot be used in load bearing applications. Furthermore, they have some prominent disadvantages which render them unsuitable for implants for use in orthopedic procedures. For example, Kapton(copyright) cannot be molded into a solid article and it contains PMDA (which, as stated above, is susceptible to hydrolysis). Ultem(copyright), which is not wholly aromatic, has relatively poor wear and fracture toughness properties. The xe2x80x9cSPxe2x80x9d systems (Vespel(copyright)) are PMDA-based and, consequently are, susceptible to hydrolysis (same structure as Kapton(copyright) which is base etched). The Hitachi PIQ(copyright) is a photoresist material applicable in electronic applications and cannot be used as a polyimide medical bearing material.
As far as non-orthopedic medical applications are concerned, Kapton(copyright) is used as flexible substrate in neuro-prosthesis devices for functionally interfacing parts of the nervous system. This micro-implant is used to assist neurological disorder. Although it was proved to be biocompatible with the human body(7), it is not used in a mechanical load bearing application.
Polyimides (e.g., 2-5 as listed above), were also used as substrates in sensory and neural structure of the cochlea. Four kinds of PIs were implanted in cat cochleas for 3 months. Histological findings showed that all four PIs were bio-compatible with mild or no inflammatory reaction to the implant. Any change was limited to the immediate vicinity of the implant(8).
Polyimide SP-21 with 15% graphite (Du Pont) was implanted into the abdominal cavity and paravertebral muscle of mongrel dogs for up to 3 years. Histological examinations showed that the PI was biocompatible with minimal tissue reaction. Local hemorrhage was noticed and no surface deterioration was visible. Weight gain after 3 years implantation was 1.45% (9), as expected when PMDA is present and the hydrolysis problem is accounted for.
A flexible electrode made of polyimide was used as an intraocular retinal prosthesis implanted in eyes. This device stimulates artificially surviving ganglion cells to replicate. The polyimide used (Kapton(copyright)), was proved as bio-compatible and non-toxic(10), but not as load bearing.
Kapton(copyright) and other polyimides were checked for blood compatibility in order to be used as encapsulants for biosensors. They were chosen because of their strong adherence to metal oxides and their organic solvent resistance. Bio-compatibility was tested in vitro on level I and II. The tests included cell culture toxicity, protein absorption, clotting times and haemolysis. No cytotoxicity or haemolysis were detected, protein absorption and clotting time were close to the results obtained from the control. The following three different polyimides were tested: Kapton(copyright), Ultem(copyright), and Siltem(copyright) (siloxane-PEI). Kapton(copyright) showed the best bio-compatibility. These results suggest that polyimides are attractive candidates as biosensor encapsulants(11).
Further evidence of polyimides bio-compatibility to blood was provided by tests for cardiopulmonary bypass and extracorporeal gas exchange membrane oxygenator, used for neonatal respiratory failure. Blood compatibility tests were performed by inserting polymer tubes into peripheral veins of mongrel dogs for 7 days. The tested polyimides showed excellent in vitro blood compatibility. Platelets hardly changed shape, and deformation and aggregation were not detected. Adsorption of plasma protein on the surface of the polyimide was negligible. No thrombus formation or fibrin precipitation were observed on the polyimide.
Considering the above described teachings, there appears to be a great need for an artificial orthopedic implant that could withstand the natural properties of the joint, thus overcoming the above problems and limitations. Furthermore, the increasing need of implanting hip prostheses in younger, more active patients, demands the development of new artificial hip joints using alternative, more advanced, suitable materials. In addition, the material to be chosen for orthopedic endo-prosthesis implantation should withstand the different loads, and resist friction and wear conditions of the human hip or knee joints. This new generation of materials should further provide a solution to late aseptic loosening, and to lesser debris generation in order to increase the duration of survival of implants.
It is an object of present invention to provide an implant, made, in part or in all, of formable, pyromellitic, dianhydride (PMDA)-free, non-halogenated, aromatic polyimide, for use in medical applications, in particular in orthopedic implantations, as well as other applications, such as, but not limited to, dental applications and cardiovascular applications.
It is a further object of the present invention to provide a process of producing a medical implant made, in part or in all, of formable, pyromellitic, dianhydride (PMDA)-free, non-halogenated, aromatic polyimide.
It is still a further object of the present invention to provide a method of implanting a medical implant made, in part or in all, of formable, pyromellitic, dianhydride (PMDA)-free, non-halogenated, aromatic polyimide.
It is yet a further object of the present invention to provide a permanent endo- and/or exo-prostheses made, in part or in all, of formable, pyromellitic, dianhydride (PMDA)-free, non-halogenated, aromatic polyimide, a process of producing same and a method of implanting same.
It is another object of the present invention to provide a an implant for joint replacement, a process of producing same and a method of implanting same.
It is yet another object of present invention to provide implants applicable in orthopedic implantation, having a high level of bio-compatibility with the surrounding tissues, strong and stable fixation of the endo-prosthesis to the bones and substantial reduction of friction and wear debris of the joint elements under dynamic load.
It is yet an additional object of present invention to provide a prosthesis that is resistant to varying stresses that may cause fatigue or wear fractures at, or close to its surface, which may result in particle detachment.
It is yet a further object of the present invention to provide a bio-compatible orthopedic implants having an extended functional lifetime, thus minimizing the need for revisions and replacements.
These and other objects of the invention will become clearer as the description proceeds.
Hence, according to one aspect of the present invention there is provided a medical implant comprising at least a portion made of a formable, pyromellitic, dianhydride (PMDA)-free, non-halogenated, aromatic polyimide.
According to another aspect of the present invention there is provided a process of producing a medical implant having at least a portion made of a formable, pyromellitic, dianhydride (PMDA)-free, non-halogenated, aromatic polyimide, the process comprising providing the polyimide in a form selected from the group consisting of powder form, granule form, pellet form and plate form; and forming the polyimide provided in the form into a predetermined desired shape. The polyimide may be formed in a net shape.
According to further features in preferred embodiments of the invention described below, forming the polyimide is effected by molding.
According to still further features in the described preferred embodiments molding is effected at a temperature ranging from about 25xc2x0 C. to about 500xc2x0 C.
According to still further features in the described preferred embodiments molding is further effected at a pressure ranging from about 100 PSI to about 20,000 PSI. According to yet another aspect of the present invention there is provided a method of implanting a medical implant in a subject, the method comprising providing a medical implant having at least a portion made of a formable, pyromellitic, dianhydride (PMDA)-free, non-halogenated, aromatic polyimide; and implanting the medical implant in the subject.
As used herein throughout, the term xe2x80x9csubjectxe2x80x9d refers to any animal having a vertebrae, mammals in particular, including human-beings.
According to further features in preferred embodiments of the invention described below, the medical implant is an orthopedic implant.
According to still another aspect of the present invention there is provided a method of treating a disorder associated with orthopedic malformation and/or disfunction and wherein an implantation of artificial implant is needed, in a subject in need of such treatment, comprising implanting in the subject an implant having at least a portion thereof made of a formable, pyromellitic, dianhydride (PMDA)-free, non-halogenated, aromatic polyimide.
According to an additional aspect of the present invention there is provided a method of treating a damaged or degenerative arthroplasty associated with malformation and/or disfunction of a joint, and wherein an implantation of an artificial joint implant is needed, in a subject in need of such treatment, comprising implanting in the subject an artificial joint implant made of formable, pyromellitic, dianhydride (PMDA)-free, non-halogenated, aromatic polyimide. Hence, in a one embodiment of the invention, the medical implant is a joint replacement prostheses.
According to further features in preferred embodiments of the invention described below, the joint is selected from the group consisting of a joints lacking a joint cavity and a synovial joint.
According to still further features in the described preferred embodiments the synovial joint is selected from the group consisting of a ball and socket joint, a hinge joint, a pivot joint, an ellipsoidal joint, a saddle joint and a gliding joint.
According to still further features in the described preferred embodiments the synovial joint is selected from the group consisting of a hip joint, a knee joint, an ankle joint, a shoulder joint, an elbow joint, a wrist joint, a finger joint, a finger metacarpal joint, a toe joint, a toe-metatarsal joint and a carpo-metacarpal joint.
According to still further features in the described preferred embodiments the entire medical implant is made of the polyimide. According to still further features in the described preferred embodiments the medical implant is selected from the group consisting of a permanent endo-prostheses and a permanent exo-prostheses.
According to still further features in the described preferred embodiments the medical implant further comprising a portion made of at least one other material.
According to still further features in the described preferred embodiments the other material is selected from the group consisting of polymers such as UHMWPE, crosslinked UHMWPE and polysulfones; ceramics such as zirconia and aluminum oxide; metals such as stainless steel, titanium alloys and Coxe2x80x94Cr alloys; materials coated with wear resistance substances including diamond and hardened metals; and the like.
According to still further features in the described preferred embodiments the polyimide has the formula (I): 
wherein:
Y and Z are each independently selected from the group consisting of a chemical bond between two adjacent aromatic rings, O, CO and substituted phenyl, where Y and Z can be linked to any free position on the adjacent aromatic ring;
X is selected from the group consisting of substituted allyl, vinyl, acetynyl, phenylethynyl and benzocyclobutenyl; and
n represents an integer equal to or greater than 1, preferably n ranges from about 1 to about 100.
According to still further features in the described preferred embodiments X is selected from the group consisting of benzocyclobutenyl, acetynyl and phenylethynyl; Y and Z are each independently selected from the group consisting of a chemical bond between two adjacent aromatic rings and O; n represents an integer ranging from about 10 to about 100; and X, Y, and Z being linked to the adjacent aromatic rings in the 3, 3xe2x80x2, 4 and 4xe2x80x2 positions.
The present invention successfully addresses the shortcomings of the presently known configurations by providing a medical implant made, in part or in all, of a formable, pyromellitic, dianhydride (PMDA)-free, non-halogenated, aromatic polyimide, having a high level of bio-compatibility with surrounding tissues, substantial reduction of friction and wear debris under dynamic load, resistant to varying stresses that may cause fatigue or wear fractures at, or close to its surface, having an extended functional lifetime and in all having a performance that far exceeds that of other known materials traditionally used in medical implants.